tbuckley/cabot-search huggingface dataset:
Phase I trial of an alpha-lactalbumin vaccine in patients with moderate- to high-risk operable triple-negative breast cancer (TNBC).
Authors: George Thomas Budd, Justin M. Johnson, Emily Esakov Rhoades, Halle C. F. Moore, Megan Lynn Kruse, Erin Elizabeth Roesch, Jame Abraham, Brenna Elliott, Donna Lach, Vincent K. Tuohy
Journal: Journal of Clinical Oncology (2022)

TPS1125 Background: Triple-negative breast cancer (TNBC) is the subtype of breast cancer with the worst prognosis and is the subtype most often associated with germline mutations of BRCA1 and certain other genes. Alpha-lactalbumin (aLA) is a milk protein that is expressed in lactating breasts but not at other times or in other normal tissues. Expression of aLA is found in approximately 70% of TNBC (Cancers PMID: 27322324) so is an attractive immunologic target for TNBC based on the “retired protein hypothesis” (Semin Immunol PMID: 31926646). Pre-clinical studies have shown that vaccination with aLA provides treatment of established and, more potently, protection from development of autochthonous tumors in transgenic murine models of breast cancer and against 4T1 transplantable breast cancer in BALB/c mice (Nat Med PMID: 20512124). We are conducting a Phase I trial in patients with early stage TNBC to demonstrate the safety of this approach and to document the ability to produce a meaningful immunologic response to aLA. Methods: Patients with ER-negative, PR-negative, HER2-negative breast cancer of pathologic stage I-III or who had residual disease after standard pre-operative systemic therapy are being entered into a Phase I trial of alpha-lactalbumin with a GMP-grade zymosan adjuvant in Montanide ISA 51 VG vehicle. Participants must be within 3 years of initiation of treatment and have no evidence of recurrence. Patients receive a total of 3 vaccinations administered once every 2 weeks with doses escalated using a 3+3 trial design. Toxic events of Common Terminology Criteria for Adverse Events (CTCAE) grade 2 or greater are considered dose-limiting. Dose levels being tested are alpha-lactalbumin/zymosan 0.01 mg/0.01 mg, 0.1 mg/0.1 mg, and 1 mg/1 mg. Patients are being monitored for toxicity until 84 days after the first vaccination or resolution of toxicity, whichever is later. Blood is being drawn prior to therapy and 14, 28, and 56 days after the first vaccination to assess cellular response using enzyme-linked immunosorbent spot (ELISpot) assays of interferon-gamma and interleukin-17 production in response to aLA. Humoral response to aLA vaccination is being assessed by enzyme-linked immunosorbent assay (ELISA). After identification of the Maximum Tolerated Dose we will expand the dose levels associated with effective tumor immunity and enroll a cohort of patients without cancer planning to undergo prophylactic bilateral mastectomy. Funding Source: Department of Defense (W81XWH-17-1-0592 and W81XWH-17-1-0593). Clinical trial information: NCT04674306.
Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer
Authors: Shanu Modi, William Jacot, Toshinari Yamashita, Joohyuk Sohn, Maria Vidal, Eriko Tokunaga, Junji Tsurutani, Naoto T. Ueno, Aleix Prat, Yee Soo Chae, Keun Seok Lee, Naoki Niikura, Yeon Hee Park, Binghe Xu, Xiaojia Wang, Miguel Gil-Gil, Wei Li, Jean-Yves Pierga, Seock-Ah Im, Halle C.F. Moore, Hope S. Rugo, Rinat Yerushalmi, Flora Zagouri, Andrea Gombos, Sung-Bae Kim, Qiang Liu, Ting Luo, Cristina Saura, Peter Schmid, Tao Sun, Dhiraj Gambhire, Lotus Yung, Yibin Wang, Jasmeet Singh, Patrik Vitazka, Gerold Meinhardt, Nadia Harbeck, David A. Cameron
Journal: New England Journal of Medicine (2022)

Among breast cancers without human epidermal growth factor receptor 2 (HER2) amplification, overexpression, or both, a large proportion express low levels of HER2 that may be targetable. Currently available HER2-directed therapies have been ineffective in patients with these "HER2-low" cancers.
Risk factors of infectious complications after benign prostatic hyperplasia surgery: Preliminary results from the retrospective and multicenter TOCUS cohort
Authors: L. Brureau, M. Chapuis, H. Robin, P. Bigot, M. Baboudjian, M. Françot, S. De Vergie, J. Rigaud, C. Jousseaume, O. Karray, F. Kosseifi, S. Borojeni, E. Lechevallier, S. Bernardeau, B. Gondran-Tellier, F. Bruyère, S. Kutchukian, M. Vallée
Journal: European Urology (2022)
Safety and efficacy of greenlight pvp in octogenarians: Evaluation of the global greenlight group database
Authors: C. Deyirmendjian, D-D. Nguyen, D. Bouhadana, K. Law, N. Bhojani, D. Elterman, B. Chughtai, F. Bruyère, L. Cindolo, G. Ferrari, C. Vasquez-Lastra, T. Borelli-Bovo, E. Becher, H. Cash, M. Reimann, E. Rijo, V. Misrai, K. Zorn
Journal: European Urology (2022)
Comprehensive genomic and clinical analysis of cancer of unknown primary site in Chinese patients.
Authors: Hongsheng Xue, Shaohua Yuan, Hui Chen, Yuman Zhang, Aodi Wang, Lei Mei, Liwei Wang, Xiaowei Dong, Kai Wang
Journal: Journal of Clinical Oncology (2022)

e15071 Background: Cancer of unknown primary (CUP) comprises 2-5% of all diagnosed cancers worldwide and is one of most common cause of death. Deep understanding of CUP plays an imported role in improving the disease diagnoses and finding the primary sites. In this study, our data revealed the genomic and clinical features of CUP in Chinese patients. Methods: FFPE samples and matched peripheral blood were collected for NGS based 450 cancer genes panel assay. Somatic variants were analyzed following CAP/CLIA-certificated workflows, including Single Nucleotide Variant (SNV), Copy Number Variation (CNV), large insertion and deletions (Lindel) and gene rearrangements. MSI status and TMB were also acquired by an NGS algorithm in house. PD-L1 status was analyzed by IHC. Results: Of the 264 CUP patients, 54.2% were male and median age was 61 years old (range, 2-88 years old). The median value of TMB was 4.6 muts/Mb (range, 0-61.2). Only 1 patient was found MSI-H status with the TMB value of 61.2 muts/Mb. In addition, 23.9% and 28.4% of the CUP patients presented PDL1 positive (&gt; 1%) and PDL1 negative respectively, with others unavailable. In the patients of available stage status, they were all advanced stage (stage ≥ III). Top metastatic sites were lymphaden (17.8%), liver(15.9%) and bone (15.5%). TP53 was the most common mutated gene (62.1%), followed by KRAS (22.3%), CDKN2A (15.9%), TERT (10.2%), EGFR (9.8%) and PIK3CA (9.8%). In the alterations of KRAS, G12D, G12V and G12C were occupied 32.2%, 28.8% and 8.4% respectively. Among the alterations of EGFR, 38.5% were L858R and 19.2% were 19del. Besides, amplification of MYC (4.9%) and 11q13 (5.3%) obviously appeared in our data. Fusion/Rearrangements of ALK and ROS1 accounted for 0.8% and 1.1% respectively . The gene alterations of tyrosine kinase were found in 48.4% of CUP patients such as ALK, BRAF, EGFR, FGFR1/2/3/4, RET, ROS1 and so on. PI3K−Akt signaling pathway and MAPK signaling pathway were the most significantly pathways (fdr &lt; 0.001) enriched in our data. A CUP patient with positive PDL1 and high TMB achieved a 9-month PFS after treatment of TP chemotherapy and immunotherapy. Conclusions: In this study, we revealed comprehensive genomic and clinical features of cancer of unknown primary site in Chinese patients. It shows promise to identify the origin anatomic site of tumor while targeted therapeutic approaches to improve outcomes.
A novel m6A-based HCC prognosis signature and potential mechanisms in predicting immune and anti-angiogenic response.
Authors: Xiang-Xu Wang, Li-Hong Wu, Qiong-Yi Dou, Qing-Qing Liu, Shi-Zhou Deng, Yajie Lu, Li-Ping Ai, Hong-Chen Ji, Wei Pan, Hong-Mei Zhang
Journal: Journal of Clinical Oncology (2022)

e16174 Background: The combination of immune checkpoint inhibitors and anti-angiogenic drugs has been approved as the preferred first-line treatment for advanced hepatocellular carcinoma (HCC). However, only a small subset of HCC patients could benefit from this combination treatment. Methods: The m6A clusters were identified by consistent cluster analysis via R package “consense-cluster plus” based on the expression of 26 m6A regulators. The immune cells infiltration was estimation of by ssGSEA, MCPCOUNT and TIMER 2.0 algorithm. The m6A-related prognosis significant genes were screened by univariate Cox, lasso-Cox and multivariate Cox regression, and the prognosis signature was constructed by multivariate Cox regression. The IC50s of anti-angiogenic drugs in GDSC (Genomics of Drug Sensitivity in Cancer) database were calculated by “pRRophetic” package. The packages “Celldex” and “SingleR” were used to annotate cell types, and to present the expression landscapes of 5 hub genes in different sites and immune cell subpopulations of HCC patients. Results: We identified three m6A clusters with distinct immune and angiogenesis microenvironments. We further constructed a 5-gene prognosis signature (termed as m6Asig-Score) which could predict both immune and anti-angiogenic responses. We illustrated that high m6Asig-Score is associated with poor prognosis, advanced TNM stage, and high TP53 mutation frequency. Besides, the m6Asig-Score was negatively associated with immune checkpoint inhibitors and anti-angiogenic drugs response. We further found that two of the five m6Asig-Score inner genes, B2M and SMOX, were associated with immune cell infiltration, immune response and the sensitivity to sorafenib, which were validated in two independent immunotherapy cohorts and the GDSC database. Conclusions: The m6Asig-Score, B2M and SMOX might have a significant impact on guiding the combined strategy of immunotherapy and anti-angiogenic therapy in HCC.
Density patterns of tumor-infiltrating lymphocytes and association with objective response to nivolumab in patients with lung adenocarcinoma from CheckMate 057.
Authors: Germán Corredor, Ruiwen Ding, Prateek Prasanna, Cristian Barrera, Paula Toro, Vidya Sankar Viswanathan, Philipp Zens, Sabina Berezowska, Vipul Baxi, David Balli, Merzu Belete, Vamsidhar Velcheti, Kurt A. Schalper, Anant Madabhushi
Journal: Journal of Clinical Oncology (2022)

2662 Background: Immune checkpoint inhibitors (ICIs) are currently approved for use as therapy in advanced stage lung adenocarcinoma (LUAD). ICIs can decrease risk of progression by up to 60% when compared to chemotherapy, but only about 20% of patients (pts) show response. Given that high levels of tumor-infiltrating lymphocytes (TILs) have been shown to be associated with better prognosis, here, we assess whether computationally derived TIL density measures on digitized H&amp;E images can predict RECIST derived response to nivolumab in LUAD in Checkmate 057 (CM057). CM057 is a clinical trial designed to compare the overall survival of metastatic non-squamous non-small cell lung cancer subjects treated with either nivolumab or docetaxel after failing platinum-based chemotherapy. Methods: H&amp;E-stained samples of 683 LUAD pts were collected from TCGA (n = 421), University of Bern (UBern) (n = 100), and CM057 (n = 162). Tumor response was assessed using RECIST v1.1. Samples were digitized as whole slide images. 294 pts randomly selected from TCGA formed the training set. The remaining 389 pts were used for validation in response to nivolumab in CM057 and prognosticating overall survival (OS) in UBern and TCGA. Computerized algorithms automatically identified TILs and extracted features related to quantity and compactness of TILs with respect to other surrounding nuclei. The top 6 features, determined by least absolute shrinkage and selection operator, were used to train Cox regression models that assign a death risk score to each patient. Pts with risk scores higher than the training median score were considered “high risk” or “non-responders” while pts with lower scores were considered “low risk” or “responders”. Results: The classifier predicted objective response in CM057 with an AUC = 0.61. Additionally, survival analysis showed that the model was prognostic for OS with hazard ratios of 2.38 (confidence interval (CI): 1.32-4.29, p = 0.01, n = 127) in TCGA and 2.37 (CI: 1.32-4.25, p &lt; 0.01, n = 100) in UBern. Conclusions: A computerized image analysis model based on measurements of TIL density showed association with response to treatment in LUAD pts who received nivolumab and was prognostic of OS. Although the AUC was not high, the results suggest analysis of TILs has potential to identify pts who will respond to treatment. Future work will include training a classifier using response to treatment as endpoint and combining the TIL measures with other biomarkers like TMB or PD-L1.
The impact of COVID-19 infection on immune-related adverse events in patients with cancer receiving immune checkpoint inhibitors.
Authors: Mengni Guo, Jieying Liu, Zohaib Ahmed, James Yu, Ruoyu Miao, Jian Guan, Mohammad Ali Esmaeil Pour, Azadeh Khayyat, Angela Grove, Manoucher Manoucheri, Mark A. Socinski, Tarek Mekhail
Journal: Journal of Clinical Oncology (2022)

2525 Background: Immune checkpoint inhibitors (ICIs) can cause a variety of inflammatory autoimmune tissue damage, referred to as immune-related adverse events (irAEs). COVID-19 is associated with increased amounts of proinflammatory cytokines, which may synergistically affect the outcome of irAEs. Data are limited regarding the impact of COVID-19 on irAEs in ICI-treated cancer patients. Methods: We retrospectively analyzed adult patients with malignant solid tumors treated with ICIs at AdventHealth Orlando between August 2020 and August 2021. All COVID-19 infections were confirmed by PCR. Patients who had the most recent ICI treatment over one month before or after the positive COVID-19 test were excluded from the study. For COVID-19 positive group, only the irAEs that developed after COVID-19 infection were considered as events. Results: A total of 579 patients were included in our study, with 46 (7.9%) in COVID-19 positive group, and 533 (92.1%) in COVID-19 negative group. The baseline characteristics of patients in the two groups were similar in terms of age, ethnicity, ECOG, cancer histology, and type of ICI. With a median follow-up of 10 months (1-73 months), no differences in the time from ICI initiation to irAE onset, corticosteroid use, or additional immunosuppressant use were seen. A trend in higher incidence of all-grade diarrhea/colitis (8.7% vs. 3.0%, p=0.07) and grade 3 and 4 hepatitis (4.3% vs. 0.8%, p=0.08) was noted in the COVID-19 positive group, however the difference was not statistically significant. No significant difference in the incidence of pneumonitis (2.2% vs. 1.1%, p=0.44), nephritis (2.2% vs. 0.8%, p=0.34) or dermatitis (6.5% vs. 6.4%, p=1.00) were noted between COVID-19 positive and negative groups. We noticed a higher incidence of all-grade irAEs in the COVID-19 positive group (30.4% vs. 19.9%, p=0.18), but the difference was not statistically significant. The incidence of grade 3 and 4 irAEs was significantly higher in the COVID-19 positive group (10.9% vs. 3.2%, p=0.02). Nine COVID-19 related death occurred while no irAE-related death was noted in the entire cohort. Conclusions: Our study suggested that COVID-19 may pose a risk of severe irAEs in cancer patients receiving ICIs. Close monitoring and possible delaying ICI administration could be considered when cancer patients were infected with COVID-19. [Table: see text]
Effect of chemotherapy in metastatic prostate cancer according to race/ethnicity groups
Authors: B. Hoeh, C. Würnschimmel, R.S. Flammia, B. Horlemann, G. Sorce, F. Chierigo, M. Wenzel, Z. Tian, F. Saad, M. Graefen, M. Gallucci, A. Briganti, C. Terrone, S. Shariat, D. Tilki, L.A. Kluth, P. Mandel, F.K.H. Chun, P. Karakiewicz
Journal: European Urology (2022)
The “Inside” Story on Tumor-Expressed PD-L1
Authors: Brent A. Hanks
Journal: Cancer Research (2022)

Abstract While the extracellular domain of PD-L1 is well-recognized for playing a critical role in immune evasion by suppressing CD8+ T-cell activity through direct PD-1 interactions, a series of studies has evolved highlighting important functional roles for the PD-L1 cytoplasmic domain in supporting various aspects of tumorigenesis. Kornepati and colleagues contribute to our overall understanding of PD-L1 in tumor biology by describing a link between tumor PD-L1 expression and DNA repair. These studies demonstrate that PD-L1 promotes breast cancer type 1 (BRCA1)–mediated homologous recombination while inhibiting cytosolic DNA sensing, thus suppressing tumor immunogenicity. Notably, these effects could not be reversed with anti-PD-L1 antibodies utilized in the clinic, suggesting that pharmacologic agents promoting PD-L1 degradation may be a more effective treatment strategy for select tumors. Studies that are improving our understanding of the pathways driven by PD-L1 cytoplasmic signaling are providing increased insight into the design of next generation combinatorial immunotherapy strategies. See related article by Kornepati et al., p. 2156
First-line therapy for elderly patients with advanced renal cell carcinoma (aRCC): A systemic review and network meta-analysis.
Authors: Yu Fujiwara, Hirotaka Miyashita, Bobby Chi-Hung Liaw
Journal: Journal of Clinical Oncology (2022)

4532 Background: Multiple regimens incorporating tyrosine kinase inhibitors (TKI) or immune checkpoint inhibitors (ICI), either alone or in combination, confer a significant OS benefit in 1L metastatic clear cell RCC. However, guidance for optimal treatment selection in elderly patients remains limited. A network meta-analysis (NMA) was performed to compare the efficacy of 1L treatments for elderly patients with aRCC. Methods: Database search was performed through Pubmed, Embase, Web of Science, and Scopus. Eligible studies were randomized controlled trials (RCTs) evaluating first-line regimens for patients with aRCC older than 65 years old. The primary outcomes were progression-free survival (PFS) and overall survival (OS). Indirect comparisons of available regimens were estimated using a random-effects NMA. Results: 14 RCTs with more than 2,100 patients and 5 RCTs with 1,529 patients were eligible for PFS and OS analyses, respectively. Compared with sunitinib (Sun), the pembrolizumab (Pem) + axitinib (Axi) (HR 0.68, 95% CI 0.48-0.97) and Pem + lenvatinib (Len) (HR 0.61, 95% CI 0.4-0.94) regimens were associated with significantly improved OS. In comparing the TKI-ICI combinations with dual ICI nivolumab (Niv) + ipilimumab (Ipi), no significant OS differences were observed (Pem + Len: HR 0.71, 95% CI 0.40-1.27; Pem + Axi: HR 0.79, 95% CI 0.47-1.34; Avelumab (Ave) + Axi: HR 1.03, 95% CI 0.58-1.85; Niv + cabozantinib [Cab]: HR 1.03, 95% CI 0.57-1.93, using Niv + Ipi as a reference). Pem + Len, Niv + Cab, Pem + Axi, and Cab alone each showed improved PFS over Sun (Table). Among these, Pem + Len showed a PFS advantage compared to Pem + Axi (HR 0.58, 95% CI 0.37-0.91), but no PFS difference compared with the other regimens (vs Niv + Cab: HR 0.63, 95% CI 0.39-1.03; vs Cab alone: HR 0.84, 95% CI 0.40-1.77). Conclusions: Pem + Len and Pem + Axi provided the largest OS benefit in elderly patients for 1L aRCC. Pem + Len showed improved PFS compared with Pem + Axi, but no difference compared with Niv + Cab or Cab alone. Further validation using real-world data is needed to confirm the efficacy and safety of first-line regimens for the geriatric population with aRCC.[Table: see text]
MEDB-46. ONC201 affects Group 3 Medulloblastoma growth by impairing cancer stem cells
Authors: Luana Abballe, Celeste Antonacci, Matteo Gianesello, Chiara Lago, Francesca Nazio, Angela Mastronuzzi, Giuseppina Catanzaro, Angela Di Giannatale, Luca Tiberi, Franco Locatelli, Evelina Miele
Journal: Neuro-Oncology (2022)

Abstract Cancer stem cells (CSCs) represent a sub-population of cancer cells capable of proliferating and generating heterogeneous cancer cell types. Acquisition of stemness features may represent a strong advantage for neoplastic cells to promote tumorigenesis and progression, driving resistance to conventional therapy and promoting disease relapse. CSCs have been discovered and isolated in major pediatric brain tumors, including medulloblastoma (MB), the most common solid malignancy in childhood. The unfolded protein response (UPR) represents an adaptation mechanism to metabolic obstacles in CSCs, able to increase tumor aggressiveness. The initial activation of the UPR is cytoprotective but the acute activation led to cell death. We found that UPR is active in MB stem cells (MBSC) and particularly in group 3 (G3). ONC201 is an imipridone compound that activates p53-independent apoptosis causing changes in gene expression similar to those caused by UPR. Here, we aim to test the in vitro efficacy of ONC201 on G3 MBSC. We selected 4 G3 MBSC (D341-Med, D283-Med, Med411, and CHLA-01-Med), for the in vitro study. Cells were choosen for their “fidelity” to the MB subgroup through the analysis of global methylation profiling, were grown in stemness conditions and expressed stemness markers at high levels. We investigated the efficacy of ONC201 treatment on CSC features, by evaluating cell viability, cell death, protein synthesis, self-renewal, and cell cycle. ONC201 treatment on G3 MB cells led to an upregulation of ATF4, a key molecule of the UPR, and the induction was stronger in MB cultured in a “stem-like” medium. Moreover, in the most MBSC analyzed, ONC201 was effective against CSCs whether by reduced cell viability, protein synthesis, and self-renewal. We also observed a trend of increased cell death. Our results suggest that ONC201 is potentially effective in treating G3 MB by compromising the stem cell compartment, and thus deserving further investigations.